An uninterrupted enteric nervous system with the preservation of myenteric ganglia is required for intestinal motility and function. Motor neurons of the myenteric ganglia predominantly express acetylcholine/tachykinins (excitatory) or nitric oxide/inhibitory peptidespurines (inhibitory) to mediate smooth muscle contraction and relaxation. Partial, selective, or total loss of nerve function and/or loss of nerve cell populations within organs and other body structures are characteristic of numerous diseases and disorders. For example, aganglionosis of various lengths of distal gut is the central pathology in Hirschsprung's disease. Enteric neuropathy is also secondary to several other disorders (e.g., diabetes, Parkinson's disease, and inflammation) resulting in gastrointestinal dysfunction. Gastrointestinal motor function is controlled by the intramural enteric nervous system. It is a complex interplay between the smooth muscle of the muscularis externa and the two enteric neuronal plexi.
Neural stem cell therapy is an emerging therapy that aims to reinstate neuronal function and thus gastrointestinal motor function by repopulating the enteric plexi. The research is driven by two significant findings: i) neural stem cells can be isolated from adult mammalian gut, including the ganglionated colon of Hirschsprung's patients; and ii) neural stem cells can be induced to differentiate into several neuronal subtypes and glia characteristic of the enteric nervous system (ENS) upon transplantation into explant cultures of agariglionic/aneural gut, or in vivo into distal colo-rectums in animal models.
While neural-crest derived enteric neural stem cells have been isolated from adult mammalian guts, including ganglionic bowel of patients with Hirschsprung's disease, there is little information or understanding of microenvironment-driven differentiation, and only limited studies describing subsequent functional behavior of these differentiated neurons in vitro. Moreover, restoration of nerve functions by neural stem cell transplantations as a treatment for nerve-loss associated disorders has not yet been clinically demonstrated, and there exists a need for methods and materials to support neuroglial cells, and to ensure phenotypic stability and long term survival of transplanted or implanted neural stem cells.